Abstract
We have recently demonstrated that nitric oxide (NO) donors can trigger either apoptosis or necrosis of neurons as a function of the intensity of the exposure. Here, we show that the apoptosis induced by the NO donors S-nitrosocysteine (SNOC) or S-nitroso-N-acetyl-penicillamine (SNAP) in cultured cerebellar granule cells (CGCs) depends on NMDA receptor (NMDA-R) activation leading to intracellular Ca2+ overload. Early dissolution of actin filaments followed by breakdown of microtubules and nuclear lamins preceded the appearance of typical apoptotic features. NO donors induced tyrosine nitration in neurons, in a small population of contaminating astrocytes, and in cultures of cerebellar astroglial cells. However, astrocytes neither displayed cytoskeletal alterations nor underwent apoptosis. Competitive and uncompetitive NMDA receptor antagonists, such as D-aminophosphonovaleric acid and MK-801, did not influence tyrosine nitration but prevented the accumulation of intracellular Ca2+, cytoskeletal breakdown, and apoptosis induced by either SNOC or SNAP in CGCs. Taken together, these data strongly suggest that Ca2+ influx through NMDA-R-gated ion channels is a critical event in CGC apoptosis induced by NO donors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Astrocytes / drug effects
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Astrocytes / metabolism
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Calcium / metabolism
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Cells, Cultured / chemistry
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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Cerebellum / cytology*
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Cysteine / analogs & derivatives
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Cysteine / pharmacology
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Cytoskeleton / metabolism*
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DNA Fragmentation / drug effects
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Dizocilpine Maleate / pharmacology
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Nitric Oxide / physiology*
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Penicillamine / analogs & derivatives
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Penicillamine / pharmacology
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Potassium / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / agonists
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / physiology*
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S-Nitroso-N-Acetylpenicillamine
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S-Nitrosothiols*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Tyrosine / metabolism
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Receptors, N-Methyl-D-Aspartate
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S-Nitrosothiols
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Nitric Oxide
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Tyrosine
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Dizocilpine Maleate
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S-Nitroso-N-Acetylpenicillamine
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S-nitrosocysteine
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Penicillamine
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Cysteine
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Potassium
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Calcium